UNIVERSITY OF KENTUCKY
Grant: $24,151 - National Institutes of Health - Jul. 29, 2009
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Award Description: Investigation into the genetic causes of the muscular dystrophies has provided unique insights into the mechanisms of several disease processes. Type II Myotonic Dystrophy is caused by a large expansion in the ZNF9 gene, which encodes the single strand RNA binding protein CNBP (Cellular Nucleic Acid Binding Protein). Remarkably, we recently discovered that CNBP is involved in regulating the activity of ?-secretase, the enzyme that produces the first cleavage event in the generation of the amyloid-? peptide (A?). The progressive fibrillization and deposition of A? is widely believed to be the primary causal factor in the development of Alzheimer's disease. Importantly, the activity and protein levels of the major ?-secretase enzyme in the brain (BACE1) increase in both Alzheimer's disease and in normal aging. This implicates regulators of BACE1 as potentially critical for the development of Alzheimer's disease, and our preliminary data suggest that CNBP may be one of these regulatory factors. Further, both BACE1 and the related peripheral enzyme BACE2 are both increased in Inclusion Body Myositis, an age-related, degenerative disease of the skeletal musculature considered by some to be a pathological cousin of Alzheimer's disease. Therefore, ?-secretase activity itself is linked to at least two age-related diseases, making the question of understanding its regulation potentially important for human health. This proposal is designed to determine the role of CNBP as a critical protein for RNA regulation and as a potential mediator of degenerative disease via the regulation of ?-secretase activity. This project focuses on three specific aims designed to (1) determine the mechanism through which CNBP regulates its targets, (2) determine what the normal function of CNBP is in the cell, and (3) determine what the role of CNBP is in disease. The project will advance through parallel stages of in vitro studies in biochemical and cell culture based model systems, up to studies in animal models of degenerative pathology. Understanding the mechanism through which CNBP operates will inform us about both basic processes in RNA regulation, and how they might go awry. These studies will lay the foundation for future advances into therapeutics to treat these diseases.
Project Description: As defined in the Award Description field.
Infrastructure Description: N/A
Jobs Summary: One undergraduate student and one science educator (both from Bridgewater College, VA) were employed in my lab this summer as a result of the ARRA supplement. As for impact, first there is the obvious contribution of employing two very capable individuals for the summer. This is an immediate and direct effect on the nation's recovery, since funds expended on this go directly into the local economy. The second effect is indirect, but is clearly beneficial: this program, through providing the experience of working in an NINDS funded laboratory, encourages individuals to pursue careers in research. Many undergraduates, even those at major research universities throughout the country, never get this opportunity. We can never have enough people working in areas of high technology, especially in areas relating to human health. In the long run, this improves our national competitiveness, by ultimately giving us better trained individuals that can help us solve som e of the more vexing problems that face us, both now and in the future. (Total jobs reported: 0)
Project Status: Completed
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